La Terapia Personalizzata in Oncologia

AZIENDA OSPEDALIERO-UNIVERSITARIA DI MODENA

1

Stato dell’ arte e prospettive della Target Therapy nei tumori mammari

PierFranco ConteDepartment of Oncology, Hematology and Respiratory Diseases

University of Modena and Reggio Emilia, Modena, Italy

La Terapia Personalizzata in OncologiaRoma, 25-26 Ottobre 2011

The Conquest of Breast Cancer: a few more steps ahead..

• A successful story ….

• Lessons froma successful story….

• Fromsize to biology:- achievements

- opportunities

- challenges

Cancer Mortality in women - Italy

Adj HT Screening

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ITALY

1951–2001

Breast

Stomach

Uterus

Lung Adj ChemoRx

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1950 1960 1970 1980 1990 2000 2010

*Mean of annual rates in the

component 6-year age groups

Source: WHO mortality and

UN population estimates

The Conquest of Breast Cancer: a few more steps ahead..

• A successful story ….

• Lessons froma successful story….

• Fromsize to biology:- achievements

- opportunities

- challenges

M.R. 62y old - May 2005Left radical mastectomy + ALNDILC, pT2 (2.3cm), N2 (14/44 N+), ER 90%, PgR 80%, HER2 1+, Ki 67 10%

May-September 2005dd chemoRx AC x 4 -> Paclitaxel x 4RT on chest wall and axylla

A nice story….

C.B. 44 y old - April 2009SE quadrantectomy + SNIDC, pT1c (1.7cm), N0, ER <1%, PgR 0%, HER2 0, Ki 67 60%

MayMay--SeptemberSeptember 20092009ChemoRxChemoRx TAC x 6TAC x 6

A sad story….

ThisThis tumortumor isis big and big and lazylazy

RT on chest wall and axyllaanastrozole for 5y

DecemberDecember 2010: NED2010: NED

RT on the RT on the breastbreast

DecemberDecember 2009: 2009: lunglung metsmets

ThisThis tumortumor isis smallsmall and and busybusy

• A successful story ….

• Lessons from a successful story:

The Conquest of Breast Cancer: a fewmore steps ahead..

lesson # 1: biology can be more important than size

• From size to biology:- achievements

- opportunities

- challenges

Adjuvant Rx of EBC - Decision -making Algorithm

Prognostic factorsAge,T, N, histology, grade, LVI, Ki-67, HR, HER2

Predictive FactorsHR, HER2

Risk assessment

Proportionalbenefit

Toxicities (short & long term)

Absolutebenefit

Patient Characteristicsand preference

Adjuvant medical treatments

Number of patients with EBC needed to treat with Adjuvant Therapy to prevent ONE recurrence

Comparison Absolute RiskReduction %

NNT

Tamoxifen vs. Nil ^ 11.8 8

Aromatase Inhibitors vs TAM* 3- 5.3 19 - 33

Aromatase Inhibitors vs Nil° ∼∼∼∼ 16 ∼∼∼∼ 6

Polychemovs. Nil ( < 50)^ 12.3 8Polychemovs. Nil ( < 50)^ 12.3 8

Polychemo vs. Nil ( 50+)^ 4.2 23

Anthra vs CMF^ 4.0 25

Taxanes vs. Anthra§ ∼ 5 20

3rd gen taxane regimen vs Nil° ∼∼∼∼ 23 ∼∼∼∼ 4

ChemoRx + Trastuzumab vs ChemoRx 6.3 - 18 6 - 15

ChemoRx + Trastuzumab vs Nil+ 13 - 35 2-3

• A successful story ….

• Lessons from a successful story:

lesson # 1: biology can be more important than size

The Conquest of Breast Cancer: a fewmore steps ahead..

lesson # 2: too many patients are treated to benefit one

lesson # 3: the “best” Rx is applied to all the patients as we are unable to predict individual treatment sensitivity

• From size to biology:- achievements

- opportunities

- challenges

The quest for personalized cancer medicine….

The Right Dose ofThe Right Dose ofThe Right Drug for

The Right Indication forThe Right Patient at

The Right Time

The Conquest of Breast Cancer: a few more steps ahead..

• A successful story ….

• Lessons froma successful story….

• Fromsize to biology:- achievements

- opportunities

- challenges

ER+65-75%

Breast Cancer Diseases – 2011

All Breast Cancers HER2+15-20%

Triple negative

15%

ER+65-75%

mTOR inhibitorsPI3K inhibitors

New agents for the breast cancer molecular subtype s

LapatinibNeratinibNeratinibPertuzumabTDM-1AntiHER2 combinationsTrastuzumab + mTORi

Triple negative15%

HER2+

15- 20 %

New cytotoxics (eribulin, ixabepilone, vinflunine)Platinum saltsBevacizumabPARP inhibitorsAntiEGFR (Cetuximab, erlotinib)Anti androgens

ER+65-75%

mTOR inhibitorsPI3K inhibitors

New agents for the breast cancer molecular subtype s

Co-Targeting mTOR and HR in HR+/HER2-ve ABC

TAMRAD1

(HR+/HER2-; prior AI)BOLERO 22

(HR+/HER2-; prior Let or Ana)

TAMTAM +

everolimusEXA +

placeboEXA +

everolimus

57 54 239 485

CBR % 42.1 61.1 p 0.045 18.0 33.4 p < 0.0001

Median PFS (m) 4.5 8.6 HR 0.53 2.8 6.9 HR 0.43

Median OS (m) 24 NR HR 0.32 NR NR

1Bachelet T et al, SABCS 2010; 2 Baselga J et al, ECCO/ESMO 2011

ER+65-75%

mTOR inhibitorsPI3K inhibitors

New agents for the breast cancer molecular subtype s

AI + antiHER2 agentsHER2+

15- 20 %

Co-Targeting HER2 and HR in HR+/HER2+ve ABC

TANDEM1 eLEcTRA 2 Johnston et al 3

ANAANA +

trastuzumabLET

LET + trastuzumab

LET +Plac

LET +lapatinib

Pts # 104 103 31 26 108 111

ORR % 6.8 20.3 p 0.018 13.0 27 p 0.3 15 28 p 0.02

median PFS (m)

2.4 4.8HR 0.63

3.3 14.1HR 0.67

3.0 8.2 HR 0.71

Median OS (m)

23.9 28.5 p 0.32 NR NR 32.3 33.3HR 0.74

p 0.1

1 Kaufman B, et al. JCO 2009; 2 Huober J et al. The Breast 2011; 3 Johnston S et al. JCO 2009

New agents for the breast cancer molecular subtype s

LapatinibNeratinibNeratinibPertuzumabTDM-1AntiHER2 combinationsTrastuzumab + mTORi

HER2+

15- 20 %

HER2+ EBCRCTs of PCT + dual antiHER2 blockade

Trial pts # Regimen pCR% (breast&N)

Neo-ALLTO1 455 wPac+T/L /TL 20 /27.6/46.9*

19

NeoSphere2 417 DT/DTP/TP/DP 21.5/39.3* /11.2/17.7

CherLob3 121 wP-FECT/L/ TL 25.7/27.8/43.1*

* p value < 0.05T = trastuzumab; L = Lapatinib; P = Pertuzumab

1Baselga J et al, SABCS 2010; 2Gianni L et al, SABCS 2010; 3Guarneri V et al, ASCO 2011

• Trastuzumab-DM1 (T-DM1) is an anti-HER2 antibody drug–conjugate 1,2

– Combines the HER2-targeting properties of trastuzumab3 with targeted delivery of a highly potent anti-microtubule derivative, DM13-5

– After binding to HER2, T-DM1 undergoes receptor-mediated internalization,6 resulting in intracellular release of DM1

20

1. Krop I, et al. J Clin Oncol 2008; 2.Burris HA, et al. J Clin Oncol, 2010; 3. Lewis Phillips, et al. Cancer Res. 2008; 4 . Junttila TT, et al. Breast Cancer Res Treat, 2010; 5. Remillard S, et al. Science 1975; 6.Austin CD, et al. 2004. Mol Biol Cell 2004

Randomized phase II study of TDM -1 vs Trastuzumab/Docetaxel in HER2+ ABC

Outcome Trastuzumab + Docetaxel

TDM-1

Patients # 70 67

CR % 4.3 10.4 CR % 4.3 10.4

PR % 53.6 53.7

OR % 57.9 64.1

SD % 33.3 19.4

median PFS (m) 9.2 14.2 HR 0.59

G > 3 AE % 89.4 46.4

Hurvitz SA, et al. ESMO 2011.

TDM4788g/BO22589 (MARIANNE): a Phase III trial of T-DM1 + pertuzumab vs trastuzumab + docetaxel in 1st L

Primary endpoints

● PFS (independent assessment)

● Safety

Secondary endpoints

● ORR (independent assessment)

HER2-positive MBC

No prior chemotherapy

(n=1092*)

Clinicaltrials.gov

● OS

● 1-year survival

● PFS

● ORR (investigator assessment)

● CBR

● TTF

● DoR

● Safety and tolerability

Trastuzumab

+ taxane

T-DM1 +

placebo

T-DM1 +

pertuzumab

FPI Jul 2010

Estimated completion: 2012

Estimated date of data availability: 2012

332 centres in 40 countries

New agents for the breast cancer molecular subtype s

Triple negative

New cytotoxics (eribulin, ixabepilone, vinflunine)Platinum saltsBevacizumabTriple negative

15%BevacizumabPARP inhibitorsAntiEGFR (Cetuximab, erlotinib)Anti androgens

DNA repair is essential for cell survival

DNA lenght per cell 2 meters

Cells per human 2 x 1013

DNA lenght per human 4 x 1013 meters

Distance fromthe Earth to the Sun 1.49 x 1011 meters

Number of return trips to the Sun 134

DNA damage/cell/day 10,000-30,000

Number of DNA damage pathways 5 (2 alleles)

Modified from H Calvert

From breakthrough…..….to clinical excellence

ER+65-75%

HER3+

IGFR1+

PI3Kmut

10%

Breast Cancer Diseases – 201…

All Breast Cancers HER2+15-20%

Triple negative

15%

IGFR1+

p95+4%

P53mut

30-40 %

FGFR1Ampl 8%

PTENloss

30-50%

BRCAMut

8%

BC subtypes : an orphan designation ?

• Breast cancer incidence in Italy: 137.8 x 105

• Breast Cancer Prevalence in Italy: 520.000

• Definition of Rare Disease: - 1/1,500 people (USA)

- 1/2,000 people (EU)- 1/2,500 people (Japan)

Predictive Biomarkers in Oncology: the slippery path from EBM to Personalized Medicine

• Our standards of care are based on EBM

• EBM provides the best approach for the average population

• Clinical genomics may allow to tailor medical interventions to the needs of the individual patient

• Challenges:

The molecular characterization of

• Challenges:– Patient consent & privacy

– BioBanking

– Identification and validation of molecular markers

– High failure rate of molecular targeted therapeutics

– New study design

– Registration, Reimbursement, Accessibility

The Quest for Personalized Cancer Medicine has only ONE answer….characterization of human tumors